PROJECTSUMMARY AutismSpectrumDisorder(ASD)describesacollectionofneurodevelopmentalabnormalitiesofvarying severitythathavebeenestimatedtoimpactmorethan1%ofAmericans,mostlymales.ASDcannegatively impactone?sabilitytocommunicateandnavigatesocialinteractions.Initsmostsevereforms,ASDalsocan leadtoself-destructive,repetitivebehaviorsthatrequireafflictedpersonsbeinstitutionalizedfortheirown safety.TheprevalenceofASDhasgrowninrecentdecades;?oneexplanationforthistrendisthatpoorly appreciatedenvironmentalfactorshaveraisedtheunderlyingincidenceofthedisorder. Earlyinuteroexposuretocirculatingmaternalantibodies(Ab)hasbeenimplicatedincreasinglyasamajor riskfactorforchildrentodevelopASD.Thismodelpositsthatmaternalantibodiesbindtoproteinsonthe surfaceofthefetalbrainandinterferewithnormaldevelopment.Itissupportedbystudiesinmiceand monkeysthathaverevealedthatserapurifiedfrommotherswithASDchildren,wheninjectedbeforeacritical pointingestation,cantriggerchangesinbrainanatomyandASD-likebehavioralphenotypesinoffspring. Indeed,>10%ofASDcasesmaybeexplainedbyfetalexposuretomaternalbrain-reactiveantibodies.Yet thismodeofpathogenesishastwosalientconsequences:1)maternalAbrepresentdetectablebiomarkersthat canindicateASDrisk,and2)ASDriskcouldbemitigatedbytreatingmotherswitha?decoyantigen?to neutralizedeleteriousantibodies.Spark2Flame(S2F)seekstodevelopclinicalproductsinbothoftheseareas. S2F?seffortstoidentifyASD-riskbiomarkersledtotheisolationofamonoclonalantibody,C6,that recognizesthetransmembraneproteinCaspr2,whichhasbeenassociatedwithASDthroughpedigree analysis.InjectingpregnantmicewithpurifiedC6causesdefectsinbrainanatomyandbehavioralphenotypes inmaleoffspring,recapitulatingthesex-biasASDshowsinhumans.TwoadditionalAb,clonedfromother mothers,alsobindCaspr2.TheseresultsarguethatCaspr2-reactiveantibodiesarepredisposingforASD. InthisPhaseISBIR,S2Fwillexaminethefeasibilityofdevelopingapredictiveclinicaldiagnosticassayfor ASD-riskbasedondetectingmaternalserumreactivitytoCaspr2.InAim1,micewillbeimmunizedwith Caspr2beforepregnancytotestthepathogenicityofpre-existing,polyclonalCaspr2antibodiesfordisrupting normalbraindevelopment.InAim2,S2Fwilldevelopaproof-of-conceptELISAmethodforrapidlyand inexpensivelydetectingCaspr2reactivityinserum.Finally,todiscoverpredictivebiomarkersforASDrisk, serumCaspr2-epitopebindingprofileswillbecomparedbetweenmothersofanormallydevelopingchildand mothersofanASDchild(Aim3).SuccessfulcompletionofthisPhaseIprojectwillidentifythemost deleteriousCaspr2-reactivematernalantibodies,whichwillfocuseffortstodevelopapredictiveclinical diagnosticassayandinformstrategiestocreateabiologictherapeutictoneutralizetheseantibodies.